Article

Dosing modifications to increase tolerability of gemcitabine and nab-paclitaxel in treatment of pancreatic cancer in the elderly.

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Abstract

441 Background: Gemcitabine and nab-paclitaxel has been reported to prolong survival in patients with metastatic pancreatic cancer. This drug combination was studied in such patients in the MPACT trial with an average age of enrolled patients being 63. Pancreatic cancer, however, is a disease of the aging with a median age at diagnosis of 70. Reductions in dosing by 20% or more in one or both components and has been shown to improve the tolerability of this regimen, thereby increasing treatment exposure. Our study aims to examine the efficacy and tolerability of this drug combination in an elderly population and how this is affected by schedule and dosing modifications. Methods: A retrospective chart review was performed of 83 patients over the age of 70 with a median age of 79 who received this drug combination as first-line treatment for pancreatic adenocarcinoma at a single institution. Overall survival and progression-free survival were assessed as well as schedule modification, dose reduction, and rates of adverse events. Results: For patients with metastatic or non-metastatic disease, the mean overall survival and progression-free survival were found to be 10.57 months and 6.63 months, respectively. When only patients with metastatic disease are analyzed, these values were found to be 9.26 months and 6.05 months, respectively, which are similar to those observed in the MPACT trial. The most common adverse events of grade 3 or greater were fatigue in 34.9% of patients and hematologic adverse events including neutropenia in 27.7% and leukopenia in 25.3% of patients. Dose reductions were commonly used to mitigate adverse events. Reductions in either one or both drugs by at least 20% occurred in 84.3% of patients. Conclusions: Gemcitabine and nab-paclitaxel in treatment of pancreatic cancer is well tolerated in an elderly population with similar rates of adverse effects when compared with previous studies, though this population experienced a significantly higher rate of fatigue. Dose reductions were used frequently in this population to improve tolerability, which may have contributed to the observed increase in overall survival in this population.

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... In line with previous studies, a higher percentage of dose reductions and discontinuations due to toxicities was seen in the full-dose arm, whereas survival and response were similar in both arms [13]. Last, a single-center study of older patients with advanced pancreatic cancer found that dose-reduced gemcitabine plus nab-paclitaxel resulted in better tolerability than standard regimen, and survival did not differ between both groups [14]. Together, these studies suggest that an adapted dose might avoid overtreatment of frail, older adults without compromising survival. ...
... The scarcity of applicable results, the specificities of this subgroup, including pharmacokinetic and pharmacodynamic changes, and the irregular access to comprehensive geriatric assessment, make metastatic pancreatic cancer treatment even more challenging (76,77). Retrospective studies have shown systemic therapy to be associated with longer OS in elderly patients, with a median OS ranging from 8 to 12 months in this subgroup, without compromising QOL (78)(79)(80). The available evidence suggests that old age should not preclude patients with good PS, adequate comorbidity profiles and social support from benefiting from protocols such as FOLFIRINOX, mFOLFIRINOX, GEM/nab-P or GEM/CAP (78,(81)(82)(83)(84). ...
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... Some of the patients required dose modification without need for drug discontinuation. [50][51][52][53] In an analysis of 237 patients with metastatic PDAC aged 75 or more, those who received systemic therapy had significantly better survival (p< 0.01) compared to those who did not, with a mean OS difference of 5.6 months. [54] These findings concur with an earlier study of 80 years and older metastatic PDAC patients, where median OS (4.9 versus 1.7 months; HR = 0.41, p < 0.0001) was significantly better in those who received treatment. ...
Article
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Pancreatic cancer represents a life threatening disease with rising mortality. Although the synergistic combination of gemcitabine and albumin-bound paclitaxel has proven to enhance the median survival rates as compared to gemcitabine alone, their systemic and repeated co-administration has been associated with serious toxic side effects and poor patient compliance. For this purpose, we designed a thermosensitive and biodegradable hydrogel encapsulating targeted nanoparticles for the local and sustained delivery of gemcitabine (GEM) and paclitaxel (PTX) to pancreatic cancer. GEM and PTX were loaded into PR_b-functionalized liposomes targeting integrin α5β1, which was shown to be overexpressed in pancreatic cancer. PR_b is a fibronectin-mimetic peptide that binds to α5β1 with high affinity and specificity. The PR_b liposomes were encapsulated into a poly(δ-valerolactone-co-D,L-lactide)-b-poly(ethylene glycol)-b-poly(δ-valerolactone-co-D,L-lactide) (PVLA-PEG-PVLA) hydrogel and demonstrated sustained release of both drugs compared to PR_b-functionalized liposomes free in solution or free drugs in the hydrogel. Moreover, the hydrogel-nanoparticle system was proven to be very efficient towards killing monolayers of human pancreatic cancer cells (PANC-1), and showed a significant reduction in the growth pattern of PANC-1 tumor spheroids as compared to hydrogels encapsulating non-targeted liposomes with GEM/PTX or free drugs, after a one week treatment period. Our hybrid hydrogel-nanoparticle system is a promising platform for the local and sustained delivery of GEM/PTX to pancreatic cancer, with the goal of maximizing the therapeutic efficacy of this synergistic drug cocktail while potentially minimizing toxic side effects and eliminating the need for repeated co-administration.
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